Antimetabolites

Question 1

Methotrexate (MTX)

Answer 1

Mechanism: Folic acid analog that inhibits dihydrofolate reductase -> decreased dTMP -> decreased DNA and decreased protein synthesis.

Clinical use: Cancers: leukemias, lymphomas, choriocarcinoma, sarcomas.
Non-neoplastic: abortion, ectopic pregnancy, rheumatoid arthritis, psoriasis.

Toxicity: Myelosuppression, which is reversible with leucovorin (folinic acid) “rescue”.
Macrovesicular fatty change in liver.
Mucositis.
Teratogenic.

Question 2

5-fluorouracil (5-FU)

Answer 2

Mechanism: Pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid.
This complex inhibits thymidylate synthase -> decreased dTMP -> decreased DNA and decreased protein synthesis.

Clinical use: Colon cancer, basal cell carcinoma (topical).

Toxicity: Myelosuppression, which is not reversible with leucovorin;
Overdose: “rescue” with thymidine.
Photosensitivity.

Question 3

Cytarabine (arabinofuranosyl cytidine)

Answer 3

Mechanism: Pyrimidine analog -> inhibition of DNA polymerase.

Clinical use: Leukemias, lymphomas.

Toxicity: Leukopenia, thrombocytopenia, megaloblastic anemia.

Question 4

Azathioprine 6-mercaptopurine (6-MP)

6-thioguanine (6-TG)

Answer 4

Mechanism: Purine (thiol) analogs -> decreased de novo purine synthesis.
Activated by HGPRT.

Clinical use: Leukemias.

Toxicity: Bone marrow, GI, liver.
Metabolized by xanthine oxidase; thus increase toxicity with allopurinol.